: Plasmodium falciparum (Pf) and P. vivax (Pv) are resurgent, with spreading resistance to affordable antimalarials, and encroachment where they had been eradicated. A safe, affordable, and effective vaccine would reverse this trend, and in vitro immunologic correlates of protection would accelerate vaccine development. The primary goal is to identify and validate an assay(s) that predicts acquired protective immunity. The investigators will exploit a unique epidemiologic situation to identify the key determinants of naturally acquired immunity. Nonimmune individuals from Java settling in hyperendemic Irian Jaya, Indonesia, acquire clinical immunity within 36 months. This allows separation of the effects of age on immunologic development from those of chronic heavy exposure to infection and provides the opportunity to longitudinally follow the acquisition of clinical immunity. The core of the proposed studies is the longitudinal clinical, parasitological, and immunological analysis of 1000 new transmigrants followed for 3 years. Immunological assays for these studies will be defined and validated on specimens obtained in cross-sectional analyses of non-immune controls in Java, and residents of 3 transmigration villages in Irian Jaya having less than 6, approximately 12, or greater than 24 months exposure (n=1600). Purified IgG from the cross- sectional studies will be assessed for affect on Pf parasitemia in Aotus monkeys to provide a benchmark of anti-parasite immunity. By identifying immunological responses that change during the transition from nonimmune to clinically immune, and controlling for genetic and environmental factors that may influence outcome (HLA, hemoglobin, and others), the investigators seek to establish an assay or set of assays that correlate with protective immunity. Immunity will be assessed as individuals transition to a state of clinical immunity. The major focus will be on antibodies against asexual erythrocytic stages that reduce parasitemia, but they will also study antibody and T cell responses against pre-erythrocytic stages; T cells against erythrocytic stages; antibodies that neutralize malaria toxin, and limit cytoadherence and rosetting; nitric oxide production; and NK T cells. By cloning, sequencing, and recombinantly expressing specific proteins from infecting parasites, the researchers will be able to assess antibodies against the infecting strain of parasite. A nested longitudinal study will follow the development of clinical immunity in infants born to malaria-naive Javanese mothers compared to those born to malaria-exposed mothers, and a case-control study will assess risk factors for severe disease (n=150). The field studies will provide a clear description of the process of development of clinical immunity to malaria and will establish the foundation for the current studies or studies with future technology to characterize assays or combinations of assays that predict protective immunity.